It is well established that CD4 + T cells are of central importance in initiating the autoimmune destruction associated with multiple sclerosis (MS) and the rodent model of MS, experimental allergic encephalomyelitis (EAE). However, a variety of other inflammatory cells, including B cells and macrophages, contribute to the events that lead to the varying degrees of myelin and axonal damage observed in this disease syndrome. Mast cells, best known for their role in allergic responses in the skin and respiratory tract, exhibit widespread distribution in many tissues throughout the body. Relevant to this application, these cells are prevalent within sites of initial T cell activation such as the spleen and lymph node. In addition, their intimate association with blood vessels and nerves and the plethora of immunoregulatory mediators that can be produced by mast cells make them viable candidates for profoundly influencing immune function. Using the myelin oligodendrocyte glycoprotein (MOG)-induced model of EAE, we recently demonstrated that mast cell-deficient mice exhibit delayed onset and less severe disease than their wild type littermates. Reconstitution of the mast cell population with wild type bone marrow mast cells, a procedure that does not correct other hematological abnormalities in these animals, restores the susceptibility to severe disease. Surprisingly, this restoration of disease susceptibility occurs without detectable reconstitution of mast cells in the CNS, revealing a role for mast cells in the periphery. These findings do not rule out the possibility that mast cells directly influence inflammatory events in the CNS in mast cell competent animals. However, they do illuminate a model for examining how mast cells can influence the generation and character of the autoimmune T cell response, independent of any CNS effects. In this application, we propose experiments to determine the sites of mast cell influence on disease course and to explore the mechanism through which mast cells exert their influence. The specific aims are as follows: 1) To determine the modes of mast cell activation in disease; 2) To characterize specific mast cell-regulated lymphoctye immune responses in EAE; 3) To determine the mediators that confer mast cell influence on disease [unreadable] [unreadable]